The mechanisms by which mononuclear phagocytes exert antimicrobial activity have been largely unexplored. Our recent studies with an in vitro Toxoplasma gondii model, however, have demonstrated that the antitoxoplasma activity of specifically immune macrophages is mediated by an oxygen-dependent system which generates oxidative metabolites beyond the production of superoxide anion (02) and hydrogen peroxide (H2O2). Using this macrophage model, we have also demonstrated a close correlation between two effects of in vitro lymphokine activation: enhanced antitoxoplasma activity and augmented oxidative capacity. These studies will now be extended to characterize the role of oxidative metabolism in macrophage antileishmanial activity by investigating the interaction of animal and human mononuclear phagocytes with two pathogenetically distinct Leishmania strains, L. tropica and L. donovani. The susceptibility of the promastigote and amastigote forms of these strains to oxygen intermediates will be examined in both cell-free and macrophage microbicidal models. Using a variety of approaches, we will investigate whether increased macrophage oxidative metabolism correlates with enhanced antileishmanial activity. We will examine: a) the oxidative capacity and antimicrobial activity of unstimulated macrophages from resistant and susceptible inbred mice and those activated by in vivo and in vitro stimuli, b) whether the macrophage oxidative response to L. tropica and L. donovani differs, c) which oxygen intermediates are responsible for mediating macrophage antileishmanial activity, and d) whether Leishmania persist intracellularly because they avoid triggering macrophage oxidative responses. These studies will provide an in depth assessment of the mechanisms underlying macrophage microbicidal activity toward intracellular Leishmania parasites.